Fever is a key element of the initial response to infection. In general, fever is associated with improved survival during infections, but the mechanisms of its protective effects are largely unknown. We hypothesize that the increase in core temperatures that occurs during febrile illnesses is essential for optimal orchestration of the host defenses. Our overall research objective is to determine the mechanisms through which increases in core temperature during fever influence morbidity and showed that increases in core temperature to febrile levels enhances the early cytokine responses to bacterial endotoxin (LPS), a non-replicating agonist. We have taken advantage of the partial ectothermic nature of young (8-10 week old) mice to develop a method to passively maintain core temperatures at febrile (39-40 degrees Celsius) or afebrile (36.5- 37.5 degrees Celsius) levels during infections. We will use this model to directly determine the following potential effects of core temperatures changes in mice infected with Klebsiella pneumoniae, a clinically relevant and virulent bacterial pathogen: (1) determine if febrile core temperatures enhance containment and reduce dissemination of K. pneumoniae peritonitis; (2) determine if increasing core temperature to febrile levels enhances collateral tissue injury during K. pneumoniae peritonitis; (3) evaluate the potential roles of altered TNFalpha expression or tissue responsiveness to TNFalpha; and (4) determine if an increase in core temperature in core temperature to febrile levels is required for optimal orchestration of the host response and survival in K. pneumoniae pneumonia. The results of the proposed research will provide important information about the mechanisms through which changes in core temperature regulate host defenses. Because technology is available to modify body temperature, the results of the proposed experiments can be rapidly translated to the clinical area. Understanding the role of core temperature in regulating host defenses may lead to new protocols for managing body temperature during infections and may identify novel modalities for treating and preventing septic shock.